Sympathetic nervous system catecholamines and neuropeptide Y neurotransmitters are upregulated in human NAFLD and modulate the fibrogenic function of hepatic stellate cells
| Autor: | Ching I. Lin, Manlio Vinciguerra, Sara Vander Borght, Valerio Pazienza, Clare Selden, Tania Roskams, Gianluigi Mazzoccoli, Maelle Morgan, Barbara Sigala, Chad McKee, Jude A. Oben, J Soeda |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Liver Cirrhosis
medicine.medical_specialty Sympathetic nervous system Sympathetic Nervous System Adrenergic receptor medicine.medical_treatment lcsh:Medicine 03 medical and health sciences Norepinephrine 0302 clinical medicine Catecholamines Downregulation and upregulation Non-alcoholic Fatty Liver Disease Transforming Growth Factor beta Internal medicine Hepatic Stellate Cells Medicine Humans Neuropeptide Y Receptor lcsh:Science Cells Cultured Chromatography High Pressure Liquid 030304 developmental biology DNA Primers 0303 health sciences Multidisciplinary Base Sequence business.industry Reverse Transcriptase Polymerase Chain Reaction Leptin Interleukins lcsh:R Neuropeptide Y receptor 3. Good health Receptors Adrenergic Up-Regulation Fatty Liver Endocrinology medicine.anatomical_structure Cytokine 030220 oncology & carcinogenesis Hepatic stellate cell lcsh:Q Collagen business Research Article |
| Zdroj: | PLoS ONE, Vol 8, Iss 9, p e72928 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Sympathetic nervous system (SNS) signalling regulates murine hepatic fibrogenesis through effects on hepatic stellate cells (HSC), and obesity-related hypertension with SNS activation accelerates progression of non-alcoholic fatty liver disease (NAFLD), the commonest cause of chronic liver disease. NAFLD may lead to cirrhosis. The effects of the SNS neurotransmitters norepinephrine (NE), epinephrine (EPI) and neuropeptide Y (NPY) on human primary HSC (hHSC) function and in NAFLD pathogenesis are poorly understood. Aims to determine the mechanistic effects of NE/EPI/NPY on phenotypic changes in cultured hHSC, and to study SNS signalling in human NAFLD livers. Methods Freshly isolated hHSC were assessed for expression of cathecholamine/neuropeptide Y receptors and for the synthesis of NE/EPI. The effects of NE/EPI/NPY and adrenoceptor antagonists prazosin (PRZ)/propranolol (PRL) on hHSC fibrogenic functions and the involved kinases and interleukin pathways were examined. Human livers with proven NAFLD were then assessed for upregulation of SNS signalling components. Results Activated hHSC express functional α/β-adrenoceptors and NPY receptors, which are upregulated in the livers of patients with cirrhotic NAFLD. hHSC in culture synthesize and release NE/EPI, required for their optimal basal growth and survival. Exogenous NE/EPI and NPY dose-dependently induced hHSC proliferation, mediated via p38 MAP, PI3K and MEK signalling. NE and EPI but not NPY increased expression of collagen-1α2 via TGF-β without involvement of the pro-fibrogenic cytokines leptin, IL-4 and IL-13 or the anti-fibrotic cytokine IL-10. Conclusions hHSC synthesize and require cathecholamines for optimal survival and fibrogenic functionality. Activated hHSC express directly fibrogenic α/β-adrenoceptors and NPY receptors, upregulated in human cirrhotic NAFLD. Adrenoceptor and NPY antagonists may be novel anti-fibrotic agents in human NAFLD. |
| Databáze: | OpenAIRE |
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